Abstract
Cell-free DNA (cfDNA) fragments, detected in blood and in other biological fluids, are released from apoptotic and/or necrotic cells. CfDNA is currently used as biomarker for the detection of many diseases such as some cancers and gynecological and obstetrics disorders. In this study, we investigated if cfDNA levels in follicular fluid (FF) samples from in vitro fertilization (IVF) patients, could be related to their ovarian reserve status, controlled ovarian stimulation (COS) protocols and IVF outcomes. Therefore, 117 FF samples were collected from women (n = 117) undergoing IVF/Intra-cytoplasmic sperm injection (ICSI) procedure and cfDNA concentration was quantified by ALU-quantitative PCR. We found that cfDNA level was significantly higher in FF samples from patients with ovarian reserve disorders (low functional ovarian reserve or polycystic ovary syndrome) than from patients with normal ovarian reserve (2.7 ± 2.7 ng/μl versus 1.7 ± 2.3 ng/μl, respectively, p = 0.03). Likewise, FF cfDNA levels were significant more elevated in women who received long ovarian stimulation (> 10 days) or high total dose of gonadotropins (≥ 3000 IU/l) than in women who received short stimulation duration (7–10 days) or total dose of gonadotropins < 3000 IU/l (2.4 ± 2.8 ng/μl versus 1.5 ± 1.9 ng/μl, p = 0.008; 2.2 ± 2.3 ng/μl versus 1.5 ± 2.1 ng/μl, p = 0.01, respectively). Finally, FF cfDNA level was an independent and significant predictive factor for pregnancy outcome (adjusted odds ratio = 0.69 [0.5; 0.96], p = 0.03). In multivariate analysis, the Receiving Operator Curve (ROC) analysis showed that the performance of FF cfDNA in predicting clinical pregnancy reached 0.73 [0.66–0.87] with 88% specificity and 60% sensitivity. CfDNA might constitute a promising biomarker of follicular micro-environment quality which could be used to predict IVF prognosis and to enhance female infertility management.
Highlights
During in vitro fertilization (IVF) procedures, the ovarian reserve status must be evaluated to optimize the ovarian response to stimulation [1,2,3]
follicular fluid (FF) Cell-free DNA (cfDNA) levels progressively increased with the infertility length and were significantly higher in patients who had been trying to conceive for more than five years compared to women who tried only for one year (2.9 ± 3.8 ng/μl versus 1.1 ± 1.6 ng/μl, p = 0.049) (Fig 1C and Table 1)
This study demonstrates that cfDNA content in pooled FF samples from the same patient is significantly related to the woman’s ovarian reserve status, suggesting that high FF cfDNA level could reflect a poor follicular micro-environment
Summary
During in vitro fertilization (IVF) procedures, the ovarian reserve status must be evaluated to optimize the ovarian response to stimulation [1,2,3]. The biomarkers currently used to assess the ovarian reserve, such as antiMüllerian hormone (AMH) and antral follicle count (AFC), are not sufficiently reliable Sometimes, these two parameters can be inconsistent because of the lack of standardization between practitioners or laboratories [5,6,7,8,9].the identification of new biomarkers that reflect more accurately the ovarian reserve status and the expected response to gonadotropin treatments might increase IVF success by improving personalized care. We have previously demonstrated that cfDNA level in individual FF samples reflects the proportion of apoptotic and necrotic cells inside ovarian follicles and varies according to the follicular size during COS [12]. FF cfDNA could represent a new biomarker of follicular microenvironment quality, and could be affected by ovarian reserve disorders and by the different COS protocols
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